High intensity interval training as a novel treatment for impaired awareness of hypoglycaemia in people with type 1 diabetes (HIT4HYPOS): a randomised parallel-group study.

AIMS/HYPOTHESIS: Impaired awareness of hypoglycaemia (IAH) in type 1 diabetes may develop through a process referred to as habituation. Consistent with this, a single bout of high intensity interval exercise as a novel stress stimulus improves counterregulatory responses (CRR) to next-day hypoglycaemia, referred to as dishabituation. This longitudinal pilot study investigated whether 4 weeks of high intensity interval training (HIIT) has sustained effects on counterregulatory and symptom responses to hypoglycaemia in adults with type 1 diabetes and IAH. METHODS: HIT4HYPOS was a single-centre, randomised, parallel-group study. Participants were identified using the Scottish Diabetes Research Network (SDRN) and from diabetes outpatient clinics in NHS Tayside, UK. The study took place at the Clinical Research Centre, Ninewells Hospital and Medical School, Dundee, UK. Participants were aged 18-55 years with type 1 diabetes of at least 5 years' duration and HbA1c levels <75 mmol/mol (<9%). They had IAH confirmed by a Gold score ≥4, modified Clarke score ≥4 or Dose Adjustment For Normal Eating [DAFNE] hypoglycaemia awareness rating of 2 or 3, and/or evidence of recurrent hypoglycaemia on flash glucose monitoring. Participants were randomly allocated using a web-based system to either 4 weeks of real-time continuous glucose monitoring (RT-CGM) or RT-CGM+HIIT. Participants and investigators were not masked to group assignment. The HIIT programme was performed for 20 min on a stationary exercise bike three times a week. Hyperinsulinaemic-hypoglycaemic (2.5 mmol/l) clamp studies with assessment of symptoms, hormones and cognitive function were performed at baseline and after 4 weeks of the study intervention. The predefined primary outcome was the difference in hypoglycaemia-induced adrenaline (epinephrine) responses from baseline following RT-CGM or RT-CGM+HIIT. RESULTS: Eighteen participants (nine men and nine women) with type 1 diabetes (median [IQR] duration 27 [18.75-32] years) and IAH were included, with nine participants randomised to each group. Data from all study participants were included in the analysis. During the 4 week intervention there were no significant mean (SEM) differences between RT-CGM and RT-CGM+HIIT in exposure to level 1 (28 [7] vs 22 [4] episodes, p=0.45) or level 2 (9 [3] vs 4 [1] episodes, p=0.29) hypoglycaemia. The CGM-derived mean glucose level, SD of glucose and glucose management indicator (GMI) did not differ between groups. During the hyperinsulinaemic-hypoglycaemic clamp studies, mean (SEM) change from baseline was greater for the noradrenergic responses (RT-CGM vs RT-CGM+HIIT: -988 [447] vs 514 [732] pmol/l, p=0.02) but not the adrenergic responses (-298 [687] vs 1130 [747] pmol/l, p=0.11) in those participants who had undergone RT-CGM+HIIT. There was a benefit of RT-CGM+HIIT for mean (SEM) change from baseline in the glucagon CRR to hypoglycaemia (RT-CGM vs RT-CGM+HIIT: 1 [4] vs 16 [6] ng/l, p=0.01). Consistent with the hormone response, the mean (SEM) symptomatic response to hypoglycaemia (adjusted for baseline) was greater following RT-CGM+HIIT (RT-CGM vs RT-CGM+HIIT: -4 [2] vs 0 [2], p<0.05). CONCLUSIONS/INTERPRETATION: In this pilot clinical trial in people with type 1 diabetes and IAH, we found continuing benefits of HIIT for overall hormonal and symptomatic CRR to subsequent hypoglycaemia. Our findings also suggest that HIIT may improve the glucagon response to insulin-induced hypoglycaemia. TRIAL REGISTRATION: ISRCTN15373978. FUNDING: Sir George Alberti Fellowship from Diabetes UK (CMF) and the Juvenile Diabetes Research Foundation.

Competing risks analysis for neutrophil to lymphocyte ratio as a predictor of diabetic retinopathy incidence in the Scottish population.

BACKGROUND: Diabetic retinopathy (DR) is a major sight-threatening microvascular complication in individuals with diabetes. Systemic inflammation combined with oxidative stress is thought to capture most of the complexities involved in the pathology of diabetic retinopathy. A high level of neutrophil-lymphocyte ratio (NLR) is an indicator of abnormal immune system activity. Current estimates of the association of NLR with diabetes and its complications are almost entirely derived from cross-sectional studies, suggesting that the nature of the reported association may be more diagnostic than prognostic. Therefore, in the present study, we examined the utility of NLR as a biomarker to predict the incidence of DR in the Scottish population. METHODS: The incidence of DR was defined as the time to the first diagnosis of R1 or above grade in the Scottish retinopathy grading scheme from type 2 diabetes diagnosis. The effect of NLR and its interactions were explored using a competing risks survival model adjusting for other risk factors and accounting for deaths. The Fine and Gray subdistribution hazard model (FGR) was used to predict the effect of NLR on the incidence of DR. RESULTS: We analysed data from 23,531 individuals with complete covariate information. At 10 years, 8416 (35.8%) had developed DR and 2989 (12.7%) were lost to competing events (death) without developing DR and 12,126 individuals did not have DR. The median (interquartile range) level of NLR was 2.04 (1.5 to 2.7). The optimal NLR cut-off value to predict retinopathy incidence was 3.04. After accounting for competing risks at 10 years, the cumulative incidence of DR and deaths without DR were 50.7% and 21.9%, respectively. NLR was associated with incident DR in both Cause-specific hazard (CSH = 1.63; 95% CI: 1.28-2.07) and FGR models the subdistribution hazard (sHR = 2.24; 95% CI: 1.70-2.94). Both age and HbA1c were found to modulate the association between NLR and the risk of DR. CONCLUSIONS: The current study suggests that NLR has a promising potential to predict DR incidence in the Scottish population, especially in individuals less than 65 years and in those with well-controlled glycaemic status.

Cardiovascular Safety in Type 2 Diabetes With Sulfonylureas as Second-line Drugs: A Nationwide Population-Based Comparative Safety Study.

OBJECTIVE: To assess the real-world cardiovascular (CV) safety for sulfonylureas (SU), in comparison with dipeptidyl peptidase 4 inhibitors (DPP4i) and thiazolidinediones (TZD), through development of robust methodology for causal inference in a whole nation study. RESEARCH DESIGN AND METHODS: A cohort study was performed including people with type 2 diabetes diagnosed in Scotland before 31 December 2017, who failed to reach HbA1c 48 mmol/mol despite metformin monotherapy and initiated second-line pharmacotherapy (SU/DPP4i/TZD) on or after 1 January 2010. The primary outcome was composite major adverse cardiovascular events (MACE), including hospitalization for myocardial infarction, ischemic stroke, heart failure, and CV death. Secondary outcomes were each individual end point and all-cause death. Multivariable Cox proportional hazards regression and an instrumental variable (IV) approach were used to control confounding in a similar way to the randomization process in a randomized control trial. RESULTS: Comparing SU to non-SU (DPP4i/TZD), the hazard ratio (HR) for MACE was 1.00 (95% CI: 0.91-1.09) from the multivariable Cox regression and 1.02 (0.91-1.13) and 1.03 (0.91-1.16) using two different IVs. For all-cause death, the HR from Cox regression and the two IV analyses was 1.03 (0.94-1.13), 1.04 (0.93-1.17), and 1.03 (0.90-1.17). CONCLUSIONS: Our findings contribute to the understanding that second-line SU for glucose lowering are unlikely to increase CV risk or all-cause mortality. Given their potent efficacy, microvascular benefits, cost effectiveness, and widespread use, this study supports that SU should remain a part of the global diabetes treatment portfolio.

Glycated Haemoglobin A1c Variability Score Elicits Kidney Function Decline in Chinese People Living with Type 2 Diabetes.

Our aim was to investigate the association of glycated haemoglobin A1c (HbA1c) variability score (HVS) with estimated glomerular filtration rate (eGFR) slope in Chinese adults living with type 2 diabetes. This cohort study included adults with type 2 diabetes attending outpatient clinics between 2011 and 2019 from a large electronic medical record-based database of diabetes in China (WECODe). We estimated the individual-level visit-to-visit HbA1c variability using HVS, a proportion of changes in HbA1c of ≥0.5% (5.5 mmol/mol). We estimated the odds of people experiencing a rapid eGFR annual decline using a logistic regression and differences across HVS categories in the mean eGFR slope using a mixed-effect model. The analysis involved 2397 individuals and a median follow-up of 4.7 years. Compared with people with HVS ≤ 20%, those with HVS of 60% to 80% had 11% higher odds of experiencing rapid eGFR annual decline, with an extra eGFR decline of 0.93 mL/min/1.73 m2 per year on average; those with HVS > 80% showed 26% higher odds of experiencing a rapid eGFR annual decline, with an extra decline of 1.83 mL/min/1.73 m2 per year on average. Chinese adults with type 2 diabetes and HVS > 60% could experience a more rapid eGFR decline.

Heterogeneity in phenotype, disease progression and drug response in type 2 diabetes.

Type 2 diabetes (T2D) is a complex chronic disease characterized by considerable phenotypic heterogeneity. In this study, we applied a reverse graph embedding method to routinely collected data from 23,137 Scottish patients with newly diagnosed diabetes to visualize this heterogeneity and used partitioned diabetes polygenic risk scores to gain insight into the underlying biological processes. Overlaying risk of progression to outcomes of insulin requirement, chronic kidney disease, referable diabetic retinopathy and major adverse cardiovascular events, we show how these risks differ by patient phenotype. For example, patients at risk of retinopathy are phenotypically different from those at risk of cardiovascular events. We replicated our findings in the UK Biobank and the ADOPT clinical trial, also showing that the pattern of diabetes drug monotherapy response differs for different drugs. Overall, our analysis highlights how, in a European population, underlying phenotypic variation drives T2D onset and affects subsequent diabetes outcomes and drug response, demonstrating the need to incorporate these factors into personalized treatment approaches for the management of T2D.

Effect of multiple episodes of acute kidney injury on mortality: an observational study.

BACKGROUND: Patients who survive an episode of acute kidney injury (AKI) are more likely to have further episodes of AKI. AKI is associated with increased mortality, with a further increase with recurrent episodes. It is not clear whether this is due to AKI or as a result of other patient characteristics. The aim of this study was to establish whether recurrence of AKI is an independent risk factor for mortality or if excess mortality is explained by other factors. METHODS: This observational cohort study included adult people from the Tayside region of Scotland, with an episode of AKI between 1 January 2009 and 31 December 2009. AKI was defined using the creatinine-based Kidney Disease: Improving Global Outcomes definition. Associations between recurrent AKI and mortality were examined using a Cox proportional hazards model. RESULTS: Survival was worse in the group identified to have recurrent AKI compared with those with a single episode of AKI [hazard ratio = 1.49, 95% confidence interval (CI) 1.37-1.63; P < 0.001]. After adjustment for comorbidities, stage of reference AKI, sex, age, medicines that predispose to renal impairment or, in the 3 months prior to the reference AKI, deprivation and baseline estimated glomerular filtration rate (eGFR), recurrent AKI was independently associated with an increase in mortality (hazard ratio = 1.25, 95% CI 1.14-1.37; P < 0.001). Increasing stage of reference AKI, age, deprivation, baseline eGFR, male sex, previous myocardial infarction, cerebrovascular disease and diuretic use were all associated with an increased risk of mortality in patients with recurrent AKI. CONCLUSIONS: Recurrent AKI is associated with increased mortality. After adjusting for patient characteristics, the increase in mortality is independently associated with recurrent AKI and is not solely explained by other risk factors.

The Relationship between AKI and CKD in Patients with Type 2 Diabetes: An Observational Cohort Study.

BACKGROUND: There are few observational studies evaluating the risk of AKI in people with type 2 diabetes, and even fewer simultaneously investigating AKI and CKD in this population. This limits understanding of the interplay between AKI and CKD in people with type 2 diabetes compared with the nondiabetic population. METHODS: In this retrospective, cohort study of participants with or without type 2 diabetes, we used electronic healthcare records to evaluate rates of AKI and various statistical methods to determine their relationship to CKD status and further renal function decline. RESULTS: We followed the cohort of 16,700 participants (9417 with type 2 diabetes and 7283 controls without diabetes) for a median of 8.2 years. Those with diabetes were more likely than controls to develop AKI (48.6% versus 17.2%, respectively) and have preexisting CKD or CKD that developed during follow-up (46.3% versus 17.2%, respectively). In the absence of CKD, the AKI rate among people with diabetes was nearly five times that of controls (121.5 versus 24.6 per 1000 person-years). Among participants with CKD, AKI rate in people with diabetes was more than twice that of controls (384.8 versus 180.0 per 1000 person-years after CKD diagnostic date, and 109.3 versus 47.4 per 1000 person-years before CKD onset in those developing CKD after recruitment). Decline in eGFR slope before AKI episodes was steeper in people with diabetes versus controls. After AKI episodes, decline in eGFR slope became steeper in people without diabetes, but not among those with diabetes and preexisting CKD. CONCLUSIONS: Patients with diabetes have significantly higher rates of AKI compared with patients without diabetes, and this remains true for individuals with preexisting CKD.

Quinine exposure and the risk of acute kidney injury: a population-based observational study of older people.

OBJECTIVES: to establish and quantify any observable association between the exposure to community prescriptions for quinine and acute kidney injury (AKI) events in a population of older adults. DESIGN: two observational studies using the same dataset, a retrospective longitudinal cohort study and a self-controlled case series (SCCS). SETTING: NHS health board in Scotland. PARTICIPANTS: older adults (60+ years) who received quinine prescriptions in Tayside, Scotland, between January 2004 and December 2015. The first study included 12,744 individuals. The SCCS cohort included 5,907 people with quinine exposure and more than or equal to one AKI event. MAIN OUTCOME MEASURED: in the first study, multivariable logistic regression was used to calculate odds ratios (ORs) for AKI comparing between episodes with and without recent quinine exposure after adjustment for demographics, comorbidities and concomitant medications. The SCCS study divided follow-up for each individual into periods 'on' and 'off' quinine, calculating incidence rate ratios (IRRs) for AKI adjusting for age. RESULTS: during the study period, 273,596 prescriptions for quinine were dispensed in Tayside. A total of 13,616 AKI events occurred during follow-up (crude incidence 12.5 per 100 person-years). In the first study, exposure to quinine before an episode of care was significantly associated with an increased probability of AKI (adjusted OR = 1.27, 95% confidence interval (CI) 1.21-1.33). In the SCCS study, exposure to quinine was associated with an increased relative incidence of AKI compared to unexposed periods (IRR = 1.20, 95% CI 1.15-1.26), with the greatest risk observed within 30 days following quinine initiation (IRR = 1.48, 95% CI 1.35-1.61). CONCLUSION: community prescriptions for quinine in an older adult population are associated with an increased risk of AKI.

A randomised controlled study of high intensity exercise as a dishabituating stimulus to improve hypoglycaemia awareness in people with type 1 diabetes: a proof-of-concept study.

AIMS/HYPOTHESIS: Approximately 25% of people with type 1 diabetes have suppressed counterregulatory hormonal and symptomatic responses to insulin-induced hypoglycaemia, which renders them at increased risk of severe, disabling hypoglycaemia. This is called impaired awareness of hypoglycaemia (IAH), the cause of which is unknown. We recently proposed that IAH develops through habituation, a form of adaptive memory to preceding hypoglycaemia. Consistent with this hypothesis, we demonstrated restoration of defective counterregulatory hormonal responses to hypoglycaemia (referred to as dishabituation) in a rodent model of IAH following introduction of a novel stress stimulus (high intensity training [HIT]). In this proof-of-concept study we sought to further test this hypothesis by examining whether a single episode of HIT would amplify counterregulatory responses to subsequent hypoglycaemia in people with type 1 diabetes who had IAH (assessed by Gold score ≥4, modified Clarke score ≥4 or Dose Adjustment For Normal Eating (DAFNE) hypoglycaemia awareness rating 2 or 3). The primary outcome was the difference in adrenaline response to hypoglycaemia following both a single episode of HIT and rest. METHODS: In this randomised, crossover study 12 participants aged between 18 and 55 years with type 1 diabetes for ≥5 years and an HbA1c <75 mmol/mol (9%) were recruited. Individuals were randomised using computer generated block randomisation to start with one episode of HIT (4 × 30 s cycle sprints [2 min recovery] at 150% of maximum wattage achieved during [Formula: see text] assessment) or rest (control). The following day they underwent a 90 min hyperinsulinaemic-hypoglycaemic clamp study at 2.5 mmol/l with measurement of hormonal counterregulatory response, symptom scores and cognitive testing (four-choice reaction time and digit symbol substitution test). Each intervention and subsequent clamp study was separated by at least 2 weeks. The participants and investigators were not blinded to the intervention or measurements during the study. The investigators were blinded to the primary outcome and blood analysis results. RESULTS: All participants (six male and six female, age 19-54 years, median [IQR] duration of type 1 diabetes 24.5 [17.3-29.0] years, mean [SEM] HbA1c 56 [3.67] mmol/mol; 7.3% [0.34%]) completed the study (both interventions and two clamps). In comparison with the rest study, a single episode of HIT led to a 29% increase in the adrenaline (epinephrine) response (mean [SEM]) (2286.5 [343.1] vs 2953.8 [384.9] pmol/l); a significant increase in total symptom scores (Edinburgh Hypoglycaemia Symptom Scale: 24.25 [2.960 vs 27.5 [3.9]; p<0.05), and a significant prolongation of four-choice reaction time (591.8 [22.5] vs 659.9 [39.86] ms; p<0.01] during equivalent hypoglycaemia induced the following day. CONCLUSIONS/INTERPRETATION: These findings are consistent with the hypothesis that IAH develops in people with type 1 diabetes as a habituated response and that introduction of a novel stressor can restore, at least partially, the adapted counterregulatory hormonal, symptomatic and cognitive responses to hypoglycaemia. TRIAL REGISTRATION: ISRCTN15236211.

Visit-to-Visit HbA1c Variability Is Associated With Cardiovascular Disease and Microvascular Complications in Patients With Newly Diagnosed Type 2 Diabetes.

OBJECTIVE: To investigate the association between visit-to-visit HbA1c variability and cardiovascular events and microvascular complications in patients with newly diagnosed type 2 diabetes. RESEARCH DESIGN AND METHODS: This retrospective cohort study analyzed patients from Tayside and Fife in the Scottish Care Information-Diabetes Collaboration (SCI-DC) who were observable from the diagnosis of diabetes and had at least five HbA1c measurements before the outcomes were evaluated. We used the previously reported HbA1c variability score (HVS), calculated as the percentage of the number of changes in HbA1c >0.5% (5.5 mmol/mol) among all HbA1c measurements within an individual. The association between HVS and 10 outcomes was assessed using Cox proportional hazards models. RESULTS: We included 13,111-19,883 patients in the analyses of each outcome. The patients with HVS >60% were associated with elevated risks of all outcomes compared with the lowest quintile (for example, HVS >80 to ≤100 vs. HVS ≥0 to ≤20, hazard ratio 2.38 [95% CI 1.61-3.53] for major adverse cardiovascular events, 2.4 [1.72-3.33] for all-cause mortality, 2.4 [1.13-5.11] for atherosclerotic cardiovascular death, 2.63 [1.81-3.84] for coronary artery disease, 2.04 [1.12-3.73] for ischemic stroke, 3.23 [1.76-5.93] for heart failure, 7.4 [3.84-14.27] for diabetic retinopathy, 3.07 [2.23-4.22] for diabetic peripheral neuropathy, 5.24 [2.61-10.49] for diabetic foot ulcer, and 3.49 [2.47-4.95] for new-onset chronic kidney disease). Four sensitivity analyses, including adjustment for time-weighted average HbA1c, confirmed the robustness of the results. CONCLUSIONS: Our study shows that higher HbA1c variability is associated with increased risks of all-cause mortality, cardiovascular events, and microvascular complications of diabetes independently of high HbA1c.

Are antidementia drugs associated with reduced mortality after a hospital emergency admission in the population with dementia aged 65 years and older?

INTRODUCTION: People with dementia experience poor outcomes after hospital admission, with mortality being particularly high. There is no cure for dementia; antidementia medications have been shown to improve cognition and function, but their effect on mortality in real-world settings is little known. This study examines associations between treatment with antidementia medication and mortality in older people with dementia after an emergency admission. METHODS: The design is a retrospective cohort study of people aged ≥65 years, with a diagnosis of dementia and an emergency hospital admission between 01/01/2010 and 31/12/2016. Two classes of antidementia medication were considered: the acetylcholinesterase inhibitors and memantine. Mortality was examined using a Cox proportional hazards model with time-varying covariates for the prescribing of antidementia medication before or on admission and during one-year follow-up, adjusted for demographics, comorbidity, and community prescribing including anticholinergic burden. Propensity score analysis was examined for treatment selection bias. RESULTS: There were 9142 patients with known dementia included in this study, of which 45.0% (n = 4110) received an antidementia medication before or on admission; 31.3% (n = 2864) were prescribed one of the acetylcholinesterase inhibitors, 8.7% (n = 798) memantine, and 4.9% (n = 448) both. 32.9% (n = 1352) of these patients died in the year after admission, compared to 42.7% (n = 2148) of those with no antidementia medication on admission. The Cox model showed a significant reduction in mortality in patients treated with acetylcholinesterase inhibitors (hazard ratio [HR] = 0.78, 95% CI 0.72-0.85) or memantine (HR = 0.75, 95% CI 0.66-0.86) or both (HR = 0.76, 95% CI 0.68-0.94). Sensitivity analysis by propensity score matching confirmed the associations between antidementia prescribing and reduced mortality. DISCUSSION: Treatment with antidementia medication is associated with a reduction in risk of death in the year after an emergency hospital admission. Further research is required to determine if there is a causal relationship between treatment and mortality, and whether "symptomatic" therapy for dementia does have a disease-modifying effect.

Mortality in people with dementia, delirium, and unspecified cognitive impairment in the general hospital: prospective cohort study of 6,724 patients with 2 years follow-up.

PURPOSE: Cognitive impairment is common in older people admitted to hospital, but the outcomes are generally poorly understood, and previous research has shown inconsistent associations with mortality depending on the type of cognitive impairment examined and duration of follow-up. This study examines mortality in older people with any cognitive impairment during acute hospital admission. PATIENTS AND METHODS: Prospective cohort of 6,724 people aged ≥65 years with a structured cognitive assessment on acute admission were included in this study. Cognitive spectrum disorder (CSD) was defined as delirium alone, known dementia alone, delirium superimposed on known dementia, or unspecified cognitive impairment. Mortality associated with different types of CSD was examined using a non-proportional hazards model with 2-year follow-up. RESULTS: On admission, 35.4% of patients had CSD, of which 52.6% died within 2 years. After adjustment for demographics and comorbidity, delirium alone was associated with increased mortality in the 6 months post-admission (HR =1.45, 95% CI 1.28-1.65) and again after 1 year (HR =1.44, 95% CI 1.17-1.77). Patients with known dementia (alone or with superimposed delirium) had increased mortality only after 3 months from admission (HR =1.85, 95% CI 1.56-2.18 and HR =1.80, 95% CI 1.52-2.14) compared with patients with unspecified cognitive impairment after 6 months (HR =1.55, 95% CI 1.21-1.99). Similar but partially attenuated associations were seen after adjustment for functional ability. CONCLUSION: Mortality post-admission is high in older people with CSD. Immediate risk is highest in those with delirium, while dementia or unspecified cognitive impairment is associated with medium- to long-term risk. These findings suggest that individuals without dementia who develop delirium are more seriously ill (have required a larger acute insult in order to precipitate delirium) than those with pre-existing brain pathology (dementia). Further research to explain the mortality patterns observed is required in order to translate the findings into clinical care.

Living at home after emergency hospital admission: prospective cohort study in older adults with and without cognitive spectrum disorder.

BACKGROUND: Cognitive spectrum disorders (CSDs) are common in hospitalised older adults and associated with adverse outcomes. Their association with the maintenance of independent living has not been established. The aim was to establish the role of CSDs on the likelihood of living at home 30 days after discharge or being newly admitted to a care home. METHODS: A prospective cohort study with routine data linkage was conducted based on admissions data from the acute medical unit of a district general hospital in Scotland. 5570 people aged ≥ 65 years admitted from a private residence who survived to discharge and received the Older Persons Routine Acute Assessment (OPRAA) during an incident emergency medical admission were included. The outcome measures were living at home, defined as a private residential address, 30 days after discharge and new care home admission at hospital discharge. Outcomes were ascertained through linkage to routine data sources. RESULTS: Of the 5570 individuals admitted from a private residence who survived to discharge, those without a CSD were more likely to be living at home at 30 days than those with a CSD (93.4% versus 81.7%; difference 11.7%, 95%CI 9.7-13.8%). New discharge to a care home affected 236 (4.2%) of the cohort, 181 (76.7%) of whom had a CSD. Logistic regression modelling identified that all four CSD categories were associated with a reduced likelihood of living at home and an increased likelihood of discharge to a care home. Those with delirium superimposed on dementia were the least likely to be living at home (OR 0.25), followed by those with dementia (OR 0.43), then unspecified cognitive impairment (OR 0.55) and finally delirium (OR 0.57). CONCLUSIONS: Individuals with a CSD are at significantly increased risk of not returning home after hospitalisation, and those with CSDs account for the majority of new admissions to care homes on discharge. Individuals with delirium superimposed on dementia are the most affected. We need to understand how to configure and deliver healthcare services to enable older people to remain as independent as possible for as long as possible and to ensure transitions of care are managed supportively.

Emergent Properties of Microbial Activity in Heterogeneous Soil Microenvironments: Different Research Approaches Are Slowly Converging, Yet Major Challenges Remain.

Over the last 60 years, soil microbiologists have accumulated a wealth of experimental data showing that the bulk, macroscopic parameters (e.g., granulometry, pH, soil organic matter, and biomass contents) commonly used to characterize soils provide insufficient information to describe quantitatively the activity of soil microorganisms and some of its outcomes, like the emission of greenhouse gasses. Clearly, new, more appropriate macroscopic parameters are needed, which reflect better the spatial heterogeneity of soils at the microscale (i.e., the pore scale) that is commensurate with the habitat of many microorganisms. For a long time, spectroscopic and microscopic tools were lacking to quantify processes at that scale, but major technological advances over the last 15 years have made suitable equipment available to researchers. In this context, the objective of the present article is to review progress achieved to date in the significant research program that has ensued. This program can be rationalized as a sequence of steps, namely the quantification and modeling of the physical-, (bio)chemical-, and microbiological properties of soils, the integration of these different perspectives into a unified theory, its upscaling to the macroscopic scale, and, eventually, the development of new approaches to measure macroscopic soil characteristics. At this stage, significant progress has been achieved on the physical front, and to a lesser extent on the (bio)chemical one as well, both in terms of experiments and modeling. With regard to the microbial aspects, although a lot of work has been devoted to the modeling of bacterial and fungal activity in soils at the pore scale, the appropriateness of model assumptions cannot be readily assessed because of the scarcity of relevant experimental data. For significant progress to be made, it is crucial to make sure that research on the microbial components of soil systems does not keep lagging behind the work on the physical and (bio)chemical characteristics. Concerning the subsequent steps in the program, very little integration of the various disciplinary perspectives has occurred so far, and, as a result, researchers have not yet been able to tackle the scaling up to the macroscopic level. Many challenges, some of them daunting, remain on the path ahead. Fortunately, a number of these challenges may be resolved by brand new measuring equipment that will become commercially available in the very near future.

Texting to Reduce Alcohol Misuse (TRAM): main findings from a randomized controlled trial of a text message intervention to reduce binge drinking among disadvantaged men.

AIMS: To test the effectiveness of a theoretically based text-message intervention to reduce binge drinking among socially disadvantaged men. DESIGN: A multi-centre parallel group, pragmatic, individually randomized controlled trial. SETTING: Community-based study conducted in four regions of Scotland. PARTICIPANTS: A total of 825 men aged 25-44 years recruited from socially disadvantaged areas who had two or more episodes of binge drinking (> 8 UK units on a single occasion) in the preceding 28 days: 411 men were randomized to the intervention and 414 to the control. INTERVENTION AND COMPARATOR: A series of 112 interactive text messages was delivered by mobile phone during a 12-week period. The intervention was structured around the Health Action Process Approach, a comprehensive model which allows integration of a range of evidence-based behaviour change techniques. The control group received 89 texts on general health, with no mention of alcohol or use of behaviour change techniques. MEASUREMENTS: The primary outcome measure was the proportion of men consuming > 8 units on three or more occasions (in the previous 28 days) at 12 months post-intervention. FINDINGS: The proportion of men consuming > 8 units on three or more occasions (in the previous 28 days) was 41.5% in the intervention group and 47.8% in the control group. Formal analysis showed that there was no evidence that the intervention was effective [odds ratio (OR) = 0.79, 95% confidence interval (CI) = 0.57-1.08; absolute reduction 5.7%, 95% CI = -13.3 to 1.9]. The Bayes factor for this outcome was 1.3, confirming that the results were inconclusive. The retention was high and similar in intervention (84.9%) and control (86.5%) groups. Most men in the intervention group engaged with the text messages: almost all (92%) replied to text messages and 67% replied more than 10 times. CONCLUSIONS: A theoretically based text-messaging intervention aimed at reducing binge drinking in disadvantaged men was not found to reduce prevalence of binge drinking at 12-month follow-up.

Uncovering behavioural diversity amongst high-strength Pseudomonas spp. surfactants at the limit of liquid surface tension reduction.

Bacterial biosurfactants have a wide range of biological functions and biotechnological applications. Previous analyses had suggested a limit to their reduction of aqueous liquid surface tensions (γMin), and here we confirm this in an analysis of 25 Pseudomonas spp. strains isolated from soil which produce high-strength surfactants that reduce surface tensions to 25.2 ± 0.1-26.5 ± 0.2 mN m-1 (the surface tension of sterile growth medium and pure water was 52.9 ± 0.4 mN m-1 and 72.1 ± 1.2 mN m-1, respectively). Comparisons of culture supernatants produced using different growth media and semi-purified samples indicate that the limit of 24.2-24.7 mN m-1 is not greatly influenced by culture conditions, pH or NaCl concentrations. We have used foam, emulsion and oil-displacement behavioural assays as a simple and cost-effective proxy for in-depth biochemical characterisation, and these suggest that there is significant structural diversity amongst these surfactants that may reflect different biological functions and offer new biotechnological opportunities. Finally, we obtained a draft genome for the strain producing the highest strength surfactant, and identified a cluster of non-ribosomal protein synthase genes that may produce a cyclic lipopeptide (CLP)-like surfactant. Further investigation of this group of related bacteria recovered from the same site will allow a better understanding of the significance of the great variety of surfactants produced by bacterial communities found in soil and elsewhere.

Epidemiology and outcomes of people with dementia, delirium, and unspecified cognitive impairment in the general hospital: prospective cohort study of 10,014 admissions.

BACKGROUND: Cognitive impairment of various kinds is common in older people admitted to hospital, but previous research has usually focused on single conditions in highly-selected groups and has rarely examined associations with outcomes. This study examined prevalence and outcomes of cognitive impairment in a large unselected cohort of people aged 65+ with an emergency medical admission. METHODS: Between January 1, 2012, and June 30, 2013, admissions to a single general hospital acute medical unit aged 65+ underwent a structured specialist nurse assessment (n = 10,014). We defined 'cognitive spectrum disorder' (CSD) as any combination of delirium, known dementia, or Abbreviated Mental Test (AMT) score < 8/10. Routine data for length of stay (LOS), mortality, and readmission were linked to examine associations with outcomes. RESULTS: A CSD was present in 38.5% of all patients admitted aged over 65, and in more than half of those aged over 85. Overall, 16.7% of older people admitted had delirium alone, 7.9% delirium superimposed on known dementia, 9.4% known dementia alone, and 4.5% unspecified cognitive impairment (AMT score < 8/10, no delirium, no known dementia). Of those with known dementia, 45.8% had delirium superimposed. Outcomes were worse in those with CSD compared to those without - LOS 25.0 vs. 11.8 days, 30-day mortality 13.6% vs. 9.0%, 1-year mortality 40.0% vs. 26.0%, 1-year death or readmission 62.4% vs. 51.5% (all P < 0.01). There was relatively little difference by CSD type, although people with delirium superimposed on dementia had the longest LOS, and people with dementia the worst mortality at 1 year. CONCLUSIONS: CSD is common in older inpatients and associated with considerably worse outcomes, with little variation between different types of CSD. Healthcare systems should systematically identify and develop care pathways for older people with CSD admitted as medical emergencies, and avoid only focusing on condition-specific pathways such as those for dementia or delirium alone.

Biofilm formation and cellulose expression by Bordetella avium 197N, the causative agent of bordetellosis in birds and an opportunistic respiratory pathogen in humans.

Although bacterial cellulose synthase (bcs) operons are widespread within the Proteobacteria phylum, subunits required for the partial-acetylation of the polymer appear to be restricted to a few γ-group soil, plant-associated and phytopathogenic pseudomonads, including Pseudomonas fluorescens SBW25 and several Pseudomonas syringae pathovars. However, a bcs operon with acetylation subunits has also been annotated in the unrelated ß-group respiratory pathogen, Bordetella avium 197N. Our comparison of subunit protein sequences and GC content analyses confirms the close similarity between the B. avium 197N and pseudomonad operons and suggests that, in both cases, the cellulose synthase and acetylation subunits were acquired as a single unit. Using static liquid microcosms, we can confirm that B. avium 197N expresses low levels of cellulose in air-liquid interface biofilms and that biofilm strength and attachment levels could be increased by elevating c-di-GMP levels like the pseudomonads, but cellulose was not required for biofilm formation itself. The finding that B. avium 197N is capable of producing cellulose from a highly-conserved, but relatively uncommon bcs operon raises the question of what functional role this modified polymer plays during the infection of the upper respiratory tract or survival between hosts, and what environmental signals control its production.

Three-Dimensional Mapping of Soil Chemical Characteristics at Micrometric Scale by Combining 2D SEM-EDX Data and 3D X-Ray CT Images.

There is currently a significant need to improve our understanding of the factors that control a number of critical soil processes by integrating physical, chemical and biological measurements on soils at microscopic scales to help produce 3D maps of the related properties. Because of technological limitations, most chemical and biological measurements can be carried out only on exposed soil surfaces or 2-dimensional cuts through soil samples. Methods need to be developed to produce 3D maps of soil properties based on spatial sequences of 2D maps. In this general context, the objective of the research described here was to develop a method to generate 3D maps of soil chemical properties at the microscale by combining 2D SEM-EDX data with 3D X-ray computed tomography images. A statistical approach using the regression tree method and ordinary kriging applied to the residuals was developed and applied to predict the 3D spatial distribution of carbon, silicon, iron, and oxygen at the microscale. The spatial correlation between the X-ray grayscale intensities and the chemical maps made it possible to use a regression-tree model as an initial step to predict the 3D chemical composition. For chemical elements, e.g., iron, that are sparsely distributed in a soil sample, the regression-tree model provides a good prediction, explaining as much as 90% of the variability in some of the data. However, for chemical elements that are more homogenously distributed, such as carbon, silicon, or oxygen, the additional kriging of the regression tree residuals improved significantly the prediction with an increase in the R2 value from 0.221 to 0.324 for carbon, 0.312 to 0.423 for silicon, and 0.218 to 0.374 for oxygen, respectively. The present research develops for the first time an integrated experimental and theoretical framework, which combines geostatistical methods with imaging techniques to unveil the 3-D chemical structure of soil at very fine scales. The methodology presented in this study can be easily adapted and applied to other types of data such as bacterial or fungal population densities for the 3D characterization of microbial distribution.